We have previously shown that tumor cell death with expression of hsp70, is potently immunogenic. However, since many melanoma antigens are also normal melanocyte differentiation antigens, anti-melanoma immunity is often accompanied by autoimmunity. In order to exploit this, we hypothesized that pro-inflammatory killing of normal cells would, under certain conditions, break tolerance to normal self antigens of that tissue and that these autoimmune responses would also target shared antigens on associated tumors. We showed that hsp- mediated killing of normal melanocytes primes self-reactive T cells able to clear metastatic melanomas but without overt autoimmunity because the T cell response was rapidly suppressed by regulatory T cells (Treg). Inclusion of additional T cell co-stimulation (CD40L) cleared larger established tumors, possibly by controlling Treg activity. A clinical trial of this approach for Stage IV melanoma is due to commence at the Mayo Clinic in the Spring of 2008 once the plasmids have been manufactured. The overall goal of this application is to define, and characterize, the immunological connectivity between autoimmune and anti-tumor responses for other normal cell types beyond the classically `highly immunogenic' melanocyte/melanoma paradigm. To address this, we generated two novel models of autoimmune disease in which the immunological responses, to the same pathogenic-like insult (hsp70-mediated inflammatory killing), are profoundly different. Our data show that the aetiology/severity of autoimmunity depends critically upon innate, organ specific cytokine responses to key initiating signals (hsp70), and can lead to very diverse adaptive T cell responses (Th17, progressive autoimmunity in the prostate, or TGF-?-dependent protective Treg, in the pancreas). These models also reveal a close mechanistic relationship between autoimmune and anti-tumor responses in these tissues. We will now build on these data to gain a better understanding of the aetiology, and treatment, of autoimmune disease by determining the cellular/molecular basis of the different responses of the prostate (Specific Aim 1) and pancreas (Specific Aim 2) to hsp70-mediated inflammatory killing. We will also develop novel approaches to tumor immunotherapy by determining whether the effector molecules/cells of autoimmunity are the same, or different from, mediators of tumor rejection and whether such effectors can treat metastatic tumors (Specific Aim 3). These experiments will have significance to a broad range of disciplines including autoimmunity, innate/adaptive immune signaling pathways and tumor immunology and will drive implementation of novel immunotherapy clinical trials for prostate and, possibly, pancreatic cancer. PUBLIC HEALTH RELEVANCE: We have shown that that pro-inflammatory killing of normal melanocytes can, under certain conditions, break tolerance to normal self antigens and that these autoimmune responses also target shared antigens on associated melanomas. The overall goal of this application is to define, and characterize, the immunological connectivity between autoimmune and anti-tumor responses for other normal cell types beyond the classically `highly immunogenic' melanocyte/melanoma paradigm. To address this, we have shown that the aetiology/severity of autoimmunity depends critically upon innate, organ specific cytokine responses to key initiating signals (hsp70), and can lead to very diverse adaptive T cell responses (Th17, progressive autoimmunity in the prostate, or TGF-2-dependent protective Treg, in the pancreas). These models also reveal a close mechanistic relationship between autoimmune and anti-tumor responses in these tissues. We will now build on these data to gain a better understanding of the aetiology, and treatment, of autoimmune disease, and we will develop novel approaches to tumor immunotherapy by determining whether the effector molecules/cells of autoimmunity are the same, or different from, mediators of tumor rejection. These experiments will have significance to a broad range of disciplines including autoimmunity, innate/adaptive immune signaling pathways and tumor immunology and will drive implementation of novel immunotherapy clinical trials for prostate and, possibly, pancreatic cancer.